gastritis the histology report m rugge et al

8/12/2019 Gastritis the Histology Report M Rugge Et Al

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Digestive and Liver Disease 43S (2011) S373S384

Gastritis: The histology report

Massimo Rugge a,b,*, Gianmaria Pennelli a, Emanuela Pilozzi c, Matteo Fassan a,Giuseppe Ingravallo d , Valentina M. Russo e, Francesco Di Mario f

On behalf of the Gruppo Italiano Patologi Apparato Digerente (GIPAD) and of the Societ Italianadi Anatomia Patologica e Citopatologia Diagnostica/International Academy of Pathology,

Italian division (SIAPEC/IAP)a

Department of Medical Diagnostic Sciences & Special Therapies (Surgical Pathology & Cytopathology Section), University of Padova, Padova, ItalybIstituto Oncologico del Veneto IOV-IRCCS, Padova, ItalycDepartment of Pathology, University of Roma La Sapienza, Roma, Italy

dDepartment of Pathological Anatomy, University of Bari, Bari, ItalyeDepartment of Pathological Anatomy, Garibaldi Hospital Catania, Italy

fDepartment of Gastroenterology, University of Parma, Parma, Italy

Abstract

Gastritis is defined as inflammation of the gastric mucosa. In histological terms, it is distinguishable into two main categories, i.e.

non-atrophic and atrophic. In the gastric mucosa, atrophy is defined as the loss of appropriate glands. There are several etiological types of

gastritis, their different etiology being related to different clinical manifestations and pathological features. Atrophic gastritis (resulting mainly

from long-standing Helicobacter pyloriinfection) is a major risk factor for the onset of (intestinal type) gastric cancer. The extent and site of theatrophic changes correlate significantly with the cancer risk. The current format for histology reporting in cases of gastritis fails to establish an

immediate link between gastritis phenotype and risk of malignancy. Building on current knowledge of the biology of gastritis, an international

group of pathologists [Operative Link for Gastritis Assessment (OLGA)] has proposed a system for reporting gastritis in terms of its stage

(the OLGA Staging System): this system places the histological phenotypes of gastritis on a scale of progressively increasing gastric cancer

risk, from the lowest (Stage 0) to the highest (Stage IV). The aim of this tutorial is to provide unequivocal information on how to standardize

histology reports on gastritis in diagnostic practice.

2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Keywords:Atrophic gastritis; Gastritis; GIPAD report; Helicobacter pylori; OLGA staging

1. Introduction

Gastritis defines any (histologically confirmed) inflamma-

tion of the gastric mucosa. Worldwide, the epidemiology

of gastritis overlaps that of Helicobacter pylori (H. pylori)

infection, which affects approximately 50% of the worlds

* Correspondence to: Massimo Rugge, MD, FACG, Chair of the Surgical

Pathology and Cytopathology Unit, Universit degli Studi di Padova, Istituto

Oncologico del Veneto IOV-IRCCS, Via Aristide Gabelli, 61, 35121 Padova,

Italia.

E-mail address:[email protected] (M. Rugge).

1590-8658/$ see front matter 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

population. More definite epidemiological information is un-

available, but the incidence of gastritis around the worldconsistently parallels peoples socio-economic status.

Assessing gastritis involves a clinical examination, serol-

ogy (pepsinogens and antibodies against infectious agents

and/or auto-antigens), endoscopy (applying standardized

biopsy protocols), and histology to distinguish between non-

atrophic and atrophic gastritis [15].

There is a large body of information to indicate that

gastric atrophy is the primary risk factor for the onset of

intestinal-type (or so-called epidemic) gastric cancer (GC)

[612]. Atrophy of the gastric mucosa (with and without


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S374 M. Rugge et al. /Digestive and Liver Disease 43S (2011) S373S384

intestinal metaplasia) is considered the field cancerization

for the development of gastric cancer. Intestinalized glands

are prone to neoplastic transformation (i.e. non-invasive or

intraepithelial neoplasia; acronyms: NiN and IEN), which

have the potential for evolving into invasive adenocarcinoma

[1317]. There is some evidence of intestinal metaplasia

also being reversible (after eradicating H. pylori infection

and/or using chemoprevention strategies), while the chancesof halting the progression of NiN to cancer are considerably

lower; high-grade NiN virtually always evolves into (or

coexists with) invasive adenocarcinoma [4,11].

In spite of the greater consistency achieved thanks to the

Sydney System and its updated 1996 Houston version, the

commonly-used nomenclature for gastritis remains inconsis-

tent. Non-standard histology reporting formats are still widely

used for gastritis and even specialists are often frustrated

by histological definitions that make it difficult to identify

candidates for clinico/endoscopic surveillance [8,10,1824].

Building on current knowledge of the natural history of

gastritis and the associated cancer risk, an international groupof gastroenterologists and pathologists (the Operative Link

for Gastritis Assessment [OLGA]) has proposed a system for

reporting gastritis in terms of stage (the OLGA Staging Sys-

tem), which arranges the histological phenotypes of gastritis

along a scale of progressively increasing gastric cancer risk,

from the lowest (OLGA stage 0) to the highest (OLGA stage

IV) [2531]. This staging framework is borrowed from the

oncology vocabulary and it applies to gastritis a histology

reporting format successfully adopted for chronic hepatitis

[32,33]. Just as a given number of portal tracts is required

for the accurate staging of hepatitis, a well-defined biopsy

sampling protocol (as recommended by the Sydney System) is

a minimum requirement for the reliable staging of gastritis[21,3436].

Gastritis is staged by combining the extent of atrophy

(scored histologically) with its topographical location (result-

ing from the mapping protocol) [27,37]. In line with the

Sydney recommendations, the OLGA staging system also

includes information on the likely etiology of the gastric

inflammatory disease (e.g.H. pylori, autoimmune, etc.).

The purpose of this tutorial is to provide a consistent frame

for routine histology reporting on cases of gastritis. Basic

lesions included in the histological spectrum of gastritis are

only briefly addressed. Based on etiological considerations,

the most common histological phenotypes of gastric inflam-mation are discussed. Moreover, given the clinical impact of

the distinction between atrophic and non-atrophic gastritis, the

OLGA staging system is described in detail to offer practical

guidance on how to approach the basic histology report.

2. Gastritis: basic morphology[18,21]

2.1. Inflammatory infiltrate: mononuclear cells

Inflammatory infiltrate consists mainly of lymphocytes

(dispersed or organized in follicular/nodular structures),

plasma cells, histiocytes, and granulocytes within the lamina

propria (and sometimes within the single glands units).

The term lymphocytic gastritis is used when lympho-

cytes are detected within the glandular epithelia; it is sugges-

tive (but not diagnostic) of an immunomediated component

of the inflammatory disease [18]. A more severe (nodular)

intra-glandular lymphocytic infiltrate destroys and/or par-

tially replaces the continuity of the glandular structure: suchlympho-epithelial lesions are almost pathognomonic of

primary gastric lymphomas (almost always associated with

H. pylori).

2.2. Inflammatory infiltrate: polymorphs (neutrophils and

eosinophils)

Active inflammation in the gastric mucosa is defined

by the presence of neutrophils (within the lamina propria

and/or the glandular lumen). A case where the eosinophils

are predominant is described as eosinophilic gastritis. The

etiopathogenesis and clinical impact of such a histologicalcategory is still not clear.

2.3. Fibrosis of the lamina propria and smooth muscle

hyperplasia

Expansion of the collagen tissue of the lamina propria

(fibrosis) is associated with the loss of glandular units and

the lesion is defined as mucosal atrophy. Fibrosis of the

lamina propria may also be focal (i.e. scarring after peptic

ulcer). Hyperplasia of the muscularis mucosae may result

from long-term PPI therapy. Smooth muscle fascicles may

push the glandular coils apart, giving rise to a pseudo-atrophic

pattern.

2.4. Hyperplasia of the columnar epithelia

All inflammatory conditions of the gastric mucosa are

associated with some degree of regenerative epithelial changes

(regenerative hyperplasia) and this is typically seen at sites

associated with erosions and peptic ulcers. Expansion of the

proliferative compartment of the gastric glands (in the neck

region) leads to foveolar hyperplasia. Chemicals (NSAID,

biliary reflux into the stomach) or infectious stimuli that

increase the cell turnover result in hyperplastic foveolae. An

atypical regeneration of the glandular neck and/or expansionof the glandular proliferative compartment may make it

difficult to differentiate regenerative from dysplastic lesions

(the so-called indefinite for non-invasive neoplasia lesions).

Changes occurring in the oxyntic epithelia as a result of

treatment with proton pump inhibitors, in response to the

acid secretion being inhibited, are sometimes considered

as hyperplastic changes, but they may simply represent a

remodeling of the epithelial structure due to cytoskeletal

rearrangements.


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M. Rugge et al. /Digestive and Liver Disease 43S (2011) S373S384 S375

2.5. Gastric mucosa atrophy

Normal gastric biopsy samples feature different popula-

tions of glands (mucosecreting or oxyntic), appropriate for

the functional compartment (antrum or corpus) from which

the specimen is obtained (i.e. appropriate glands) [3840]

(Fig. 1). Occasionally, minuscule foci of metaplastic (goblet)

cells may be encountered in the foveolar epithelium (i.e.foveolar-restricted intestinal metaplasia), but the overall

density of appropriate glands is not affected.

The current definition of gastric atrophy is loss of

appropriate glands. In accordance with this definition, an

international group of gastrointestinal pathologists arranged

the histological spectrum of atrophic changes into a formal

classification (Table 1).

Different phenotypes of atrophic transformation may be

encountered, i.e.

Fig. 1. Normal and atrophic glandular units in the stomach. Different types of gastric native mucosa are shown in the top (yellow line indicates mucosecreting

antral glands; green line indicates oxyntic glands; in between, the transitional mucosa shows both oxyntic and mucosecreting commitment). Atrophic changes

occuring in the different types of gastric mucosa are also shown: (A) Shrinkage of an antral glandular unit coexisting with fibrotic lamina propria; (B) Intestinal

metaplasia of antral (mucosecreting) gland (blue line indicates IM); (C) Metaplastic antralization of oxyntic gland (pseudopyloric metaplasia = yellow line);

(D) Shrinkage of an oxyntic glandular unit, partially replaced by fibrotic lamina propria. Pseudopyloric metaplastic glands may further undergo intestinalization

(C B).

Table 1

Atrophy in the gastric mucosa: histological classification and grading

ATROPHY

0. Absent (= score 0)

1. Indefinite (no score is applicable)

2. Present Histological type Location & key lesions Grading

Antrum Corpus

2.1. Non-metaplastic Gland disappearance (shrinking) 2.1.1. Mild = G1 (130%)

Fibrosis of the lamina propria 2.1.2. Moderate = G2 (3160%)

2.1.3. Severe = G3 (>60%)

2.2. Metaplastic Metaplasia: Metaplasia: 2.2.1. Mild = G1 (130%)

Intestinal Pseudo-pyloric 2.2.2. Moderate = G2 (3160%)

Intestinal 2.2.3 Severe = G3 (>60%)

(1) Shrinkage or complete disappearance of glandular

units, replaced by expanded (fibrotic) lamina propria. Such

a situation results in a reduced glandular mass, but does not

imply any modification of the original cell phenotype (Fig. 1).

Sometimes (particularly in H. pylori-associated gastritis),

severe inflammation obscures the glands population, making

a reliable assessment of mucosal atrophy impossible. Such

cases can be (temporarily) labeled as indefinite for atrophyand the final judgment can be deferred until the inflammation

has regressed (e.g. after eradication of the H. pyloriinfection);

(2) Replacement of the native glands by metaplastic glands

featuring a new commitment (= intestinal and/or pseudo-

pyloric metaplasia). The number of glands is not necessarily

lower, but the metaplastic replacement of native glands results

in fewer glandular structures being appropriate for the

compartment concerned. Such a condition is consistent with

the definition of loss of appropriate glands (Fig. 1).


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Metaplasia is a transformation of the native commitment

of a cell (never associated with dedifferentiation) and any

metaplastic transformation of the gastric glands implies loss of

the appropriate glandular population (and therefore atrophy).

There are two main types of gastric gland metaplasia. Pseudo-

pyloric metaplasia (or spasmolytic polypeptide-expressing

metaplasia [SPEM]) of the oxyntic epithelia is characterized

by antral-like mucosa obtained from what was anatomicallycorpus mucosa [4143]. It is particularly important for the

endoscopist to identify the location of the biopsy specimens

otherwise the pathologist is likely to miss the fact that

this antral-like mucosa is metaplastic. The original oxyntic

commitment of a pseudo-pyloric epithelium can be revealed

by immunostaining for pepsinogen I (which is only found in

oxyntic mucosa).

Intestinal metaplasia (IM) may arise in native mucose-

creting (antral) epithelia or in previously-antralized oxyntic

glands (pseudo-pyloric metaplasia). Different subtypes of in-

testinal metaplasia have been classified, based on whether

the metaplastic epithelium phenotype resembles large bowelepithelia (colonic-type intestinal metaplasia) or the small in-

testinal mucosa [17,18]. In routine histology, subtyping IM

by applying specific histochemical stains (high-iron diamine

[HID]) is not recommended. Consistent data are available to

demonstrate that the extent of gastric mucosa intestinalization

parallels the histochemical demonstration of type IIIII IM

(colonic-type metaplasia).

2.6. Endocrine (enterochromaffin-like) cell hyperplasia

Endocrine cell hyperplasia is most frequently secondary

to gastric hypo/achlorhydria as a result of oxyntic atro-

phy. Hyperplasia of the endocrine enterochromaffin-like cells(ECL) may be micronodular or diffuse. Less frequently,

(neuro)endocrine (nodular) tumors (well-differentiated en-

docrine tumors; i.e. Type I carcinoids) may develop. It is

important to mention that such tumors often regress after the

source of gastrin has been removed (i.e. by antral resection)

and they almost never metastasize (these lesions have been

extensively addressed in this issue of Digestive and Liver

Diseaseby Rindi et al. [44]).

2.7. Non-invasive neoplasia (formerly dysplasia; synonym:

intraepithelial neoplasia)

In long-standing (atrophic) gastritis, mainly due to H. py-

lori infection, the metaplastic (intestinalized) epithelia are

prone to further transformation, which may result in a

dedifferentiated epithelium. This particular phenotype was

once defined as dysplasia. Dysplastic epithelia are confined

within the basal membrane of the native glandular structure.

In dysplastic epithelia, molecular studies have consistently

demonstrated a number of genotypic alterations similar to

those detectable in cancer cells. The biological similarity

between dysplasia and cancer has led to dysplasia being

renamed as non-invasive (or intraepithelial) neoplasia (i.e.

neoplasia confined by a continuous basal membrane) [19,20].

The continuity/integrity of the basal membrane separates the

neoplastic epithelia from the stroma (i.e. lamina propria).

This topographical separation rules out the stromal invasion

required for any metastatic spread.

3. Gastritis classification[5]

Current classifications of gastritis are based on etiology.

Table 2 summarizes the classification of gastritis etiologies,

also illustrating their most frequent clinical presentations and

their non-atrophic or atrophic phenotype.

4. Main forms of gastritis[18,21,39]

4.1. Helicobacter pylori gastritis

H. pylori is by far the most common etiological agent

in gastritis. At histology, the bacterium is usually detectable(by Giemsa staining modified for H. pylori) within the mu-

cous gel layer covering the gastric mucosa. H. pylori may

be difficult to detect (even with special stains) in cases of

extensive intestinal metaplasia, or during antisecretory (PPI)

therapy; in such cases, the H. pyloriinfection is suggested by

the presence of both mononuclear and neutrophilic (active)

inflammation. After successful eradication therapy, the neu-

trophils quickly disappear and any persistence of neutrophils

and/or mononuclear infiltrate are an indication of the failure

of the treatment. In routine diagnostic practice, any semi-

quantitative score of the bacteriums density has no clinically

significant implications and a distinction between H. pylori

negative versus positive status is considered adequate.H. pylori infection is a major cause of gastric atrophy.

Atrophic changes (both metaplastic and non-metaplastic) de-

tected in a biopsy sample obtained from both the angularis

incisura and the antral mucosa should first be seen as evidence

of a H. pylori gastritis. In long-standing infection (i.e. in el-

derly people) or in young patients with the infection and con-

comitant risk factors, atrophic changes also typically occur in

the oxyntic mucosa as pseudo-pyloric metaplasia, often coex-

isting with multifocal intestinal metaplasia (in the antrum and

corpus). Such patients are at greater risk of gastric cancer [21].

4.2. Chemical gastritis/gastropathies

Duodenal (bile) reflux into the stomach (due to partial

gastrectomy or dysmotility), aspirin (or other nonsteroidal

anti-inflammatory drugs), and other chemical injuries (pos-

sibly alcohol, etc.) may result in a broad spectrum of

histological mucosal lesions, associated with low-grade in-

flammation of the gastric mucosa. Given the mild nature of

the inflammatory trait, these conditions are currently defined

as chemical gastritis or gastropathies.

Exposure of the gastric mucosa to a noxious chemical

environment accelerates the turnover of the gastric epithelium,

consistently resulting in foveolar hyperplasia. A concomitant


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Table 2

Etiological classification of gastritis

Etiological category Agents Specific etiology Clinical presentation Notes

Transmissible agents Virus Cytomegalovirus Acute Non-atrophic**

Herpes virus Acute Non-atrophic **

Bacteria Helicobacter pylori Acute or chronic Non-atrophic & atrophic, type B***

Mycobacterium tuberculosis ? Acute Non-atrophic*

Mycobacterium avium complex ? Acute Non-atrophic*Mycobacterium diphtheriae Acute Non-atrophic*

Actinomyces Acute Non-atrophic*

Spirochetes Acute Non-atrophic *

Fungi Candida Acute Non-atrophic**

Histoplasma Acute Non-atrophic*

Phycomycosis Acute Non-atrophic*

Parasites Cryptosporidium Acute Non-atrophic*

Strongyloides Acute Non-atrophic*

Anisakiasis Acute Non-atrophic*

Ascaris lumbricoides Acute Non-atrophic*

Chemical agents Environment Dietary factors Chronic Non-atrophic & atrophic***

(most frequently (dietary & drug-related) Drugs: NSAIDs, ticlopidine Acute Non-atrophic; type C***

gastropathies) Alcohol Acute Non-atrophic; type C**

Cocaine Acute Non-atrophic; type C*

Bile (reflux) Acute or chronic chronic chronic Non-atrophic; type C***

Physical agents Radiation Acute or chronic Non-atrophic and atrophic*

Immuno-mediated Different pathogenesis Autoimmune Chronic Atrophic (corpus); type A**

Drugs (ticlopidine) Acute

? Gluten Chronic Lymphocytic gastritis**

Food sensitivity Acute or chronic Eosinophilic gastritis**

H. pylori(autoimmune component) Chronic Non-atrophic & atrophic

GVHD Acute or chronic Non-atrophic & atrophic*

Idiopathic Acute or chronic

Idiopathic Crohns disease ? Chronic Non-atrophic/focal atrophy**

Sarcoidosis ? Chronic Non-atrophic or focal atrophy*

Wegeners granulomatosis ? Chronic Non-atrophic or focal atrophy*

Collagenous gastritis Acute Non-atrophic*

Prevalence: ***high, **low, *very low.

histamine-mediated vascular response and the release of other

pro-inflammatory cytokines produce vascular ectasia, edema,

muscularis mucosa hyperplasia and variable mucosal fibrosis.

Most chemical gastropathies are asymptomatic, but multiple

(endoscopically detectable) erosions or ulcers may develop in

some cases, even with bleeding. Atrophic changes are rare

and histology usually features a puzzle of low-grade lesions

such as inter-foveolar edema, foveolar hyperplasia, muscularis

mucosa hyperplasia, and vascular ectasia.

4.3. Autoimmune gastritis

Autoimmune gastritis is typically restricted to the corpus

(autoimmune aggression targeted on parietal cells associated

with anti-parietal cell and anti-intrinsic factor antibodies).

The full-blown clinical syndrome includes hypo/achlorhydria,

hypergastrinemia, a low pepsinogen I/pepsinogen II ratio

(which parallels the loss of the oxyntic gland population), and

vitamin B12-deficient macrocytic anemia. Serum gastrin 17

levels frequently increase. The disease may coexist with other

immuno-mediated diseases, such as Hashimotos thyroiditis,

insulin-dependent diabetes, and vitiligo.

In the early (non-atrophic) stage, the oxyntic mucosa shows

a dense, full-thickness lymphocytic infiltrate. In a later (at-

rophic) stage, the oxyntic glands are replaced by metaplastic

glandular units (pseudo-pyloric metaplasia at first, followed

by the glands intestinalization later on). Immunohistochem-

istry for pepsinogen I reveals the native nature of the pseudo-

pyloric metaplastic glands (focally maintaining their chimeri-

cal ability to pepsinogen I secretion). Hypo/achlorhydria trig-

gers gastrin hypersecretion (hyperplasia of gastrin-secreting

cells in the antral mucosa with increased gastrin 17 levels),

which stimulates the enterochromaffin-like (ECL) cells of the

oxyntic compartment. Such a situation may result in ECLcell hyperplasia (both linear and micronodular); micronodular

ECL cell hyperplasia may progress into well-differentiated

endocrine tumor (type I carcinoid) [24,25]. Extensive gastric

metaplastic atrophy is a risk factor for adenocarcinoma. H. py-

loriinfection may coexist with autoimmune gastritis, and this

condition is an additional factor for atrophic transformation

and, as a consequence, for GC.

In clinical practice, the prevalence of the other gastritis

etiologies is practically negligible. The majority of viral,

bacterial and mycotic types of gastritis are associated with

immunodeficiency and they are not significantly involved in

the gastric oncogenetic pathway.


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5. Gastritis staging: the OLGA system[27]

Gastritis can be assessed on two different levels. The

basic level consists in recognizing and scoring the elementary

lesions (mononuclear infiltrate, activity, glandular atrophy,

etc.) assessed in a single biopsy. A higher level considers

the topography, the extent and combination of the changes

seen in single biopsy samples, and this assessment should berepresentative of the stomach disease as a whole.

Based on the assumption that a different extent and topo-

graphical distribution of atrophy expresses different clinico-

biological situations (associated with a different cancer risk),

the Houston-updated Sydney System established that multiple

biopsy samples should be obtained to explore the different

mucosa compartments [21]. Different biopsy locations have

been recommended in the international literature for map-

ping the mucosa, all of them consistent with the general

assumption that both the oxyntic and the antral mucosa have

to be explored, and that the incisura angularis is highly

informative for the purpose of establishing the earliest onsetof atrophic-metaplastic transformation [35]. The OLGA ap-

proach (basically consistent with the Houston-updated biopsy

protocol [21]) recommends at least 5 biopsy samples from: 1)

the greater and lesser curvatures of the distal antrum (A1A2

= mucus-secreting mucosa); 2) the lesser curvature at the in-

cisura angularis(A3), where the earliest atrophic-metaplastic

changes tend to occur; and 3) the anterior and posterior walls

of the proximal corpus (C1C2 = oxyntic mucosa) (Fig. 2).

The information obtained enables patients to be placed

somewhere along the path that leads chronic gastritis from the

originally reversible inflammatory lesions (mainly limited to

the antrum) to the atrophic changes extensively involving both

functional compartments (antrum and corpus) and associatedwith a high risk of GC [34].

5.1. Biopsy sampling protocol, histology request form and

biopsy handling

The approach to assessing gastritis is both clinical and

histological: clinical features should always support the

interpretation of the endoscopic and histological findings.

Fig. 2. Gastric biopsy sampling protocol.

Standardized biopsy protocols should be used, but many

different biopsy sampling protocols have been proposed [4,8].

The most widely applied is the Sydney System protocol, in

which mucosa from the oxyntic, antral, andincisura angularis

areas are sampled (Fig. 1); the need to take additional

specimens from any focal lesions has to be considered [9].

Antral and incisura angularis specimens can generally be

placed in the same bottle, the corpus biopsies in another.If more extensive sampling of the corpus is done (e.g. 2

lesser curve and 2 greater curve specimens), then three

bottles should be used (bottle 1= containing the 2 antral

samples and the sample obtained from the incisura angularis;

bottle 2: containing the 2 oxyntic samples from the anterior

and posterior gastric wall; bottle 3: containing the samples

obtained from the corpus mucosa samples obtained from the

lesser and greater curvature).

Biopsy material should be handled as little as possible and,

after fixation, it should be embedded on its edge. The basic

stains to use are H&E and modified Giemsa (for H. pylori)

[10,11].Ideally, the histology request should be a dedicated form. It

should include essential notes on the patients clinical history

and endoscopic features, and the biopsy sampling map.

Non-invasive test findings (if any) should also be reported,

e.g. pepsinogen levels, since pepsinogen (Pg) I occurs in

fundic chief cells, while PgII is present in the antrum and

corpus [13,14]. Gastrin 17 levels provide information on acid

secretion (high gastrin serum levels = low acid secretion; low

gastrin serum levels = typically means a high acid secretion).

Testing for anti-parietal cell antibodies helps in the diagnosis

of autoimmune gastritis.

The OLGA histology report also includes etiological

information obtainable from the tissue samples available (i.e.H. pylori infection; autoimmune disease, etc.).

5.2. How to apply the OLGA staging system to gastritis

The OLGA system considers gastric atrophy as the lesion

that indicates disease progression. The stage of gastritis

is obtained by combining the extent of atrophy as scored

histologically with the site(s) of atrophy identified by multiple

biopsies (Fig. 3).

The following paragraphs are intended as a concise OLGA

staging system users manual. Visual analog scales (VAS)

are used to give an example of how the different changes seenat each of the biopsy sampling levels can be pieced together

to stage a given patient (Figs. 49).

5.3. Scoring atrophy (loss of appropriate glands) at single

biopsy level

In each biopsy, atrophy is scored as the percentage of

atrophic glands. Ideally, atrophy is assessed on perpendic-

ular (full-thickness) mucosal sections. Non-metaplastic and

metaplastic subtypes are considered together. For each biopsy

sample (whatever the area it comes from), atrophy is scored

on a four-tiered scale (no atrophy, 0%, score = 0; mild


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Fig. 3. The OLGA staging frame.

atrophy, 130%, score = 1; moderate atrophy, 3160%, score

= 2; severe atrophy,>60%, score = 3). These scores (03) are

used in the OLGA staging assessment (Fig. 3).

5.4. Assessing atrophy in each compartment (mucosecretingand oxyntic)

According to the Sydney protocol, 3 biopsy samples should

be taken from the mucosecreting area (2 antral samples + 1

from theincisura angularis), and 2 from the oxyntic mucosa.

It is important to note that atrophic transformation in samples

of incisura angularis mucosa is only assessed in terms of

glandular shrinkage (with fibrosis of the lamina propria) or

intestinal metaplasia (replacing original mucosecreting and/or

oxyntic glands).

In each of the 2 mucosal compartments (mucosecreting and

oxyntic), an overall atrophy score expresses the percentage of

compartmental atrophic changes (pooling the findings in biop-sies obtained from the same functional compartment). The

same cut-offs are used at this higher assessment level as for

single biopsies (no atrophy, 0%, score = 0; mild atrophy, 1

30%, score = 1; moderate atrophy, 3160%, score = 2; severe

atrophy, >60%, score = 3). Using this strategy, an overall at-

rophy score is obtained that separately summarizes the scores

for the mucosa in the antrum ([Aas] Aas0, Aas1, Aas2, Aas3)

and the corpus ([Cas] Cas0, Cas1, Cas2, Cas3) (Figs. 49).

The OLGA stage is obtained by combining the overall

antrum score with the overall corpus score (Fig. 3).

6. From atrophy score to OLGA stage[27]

6.1. Stage 0 gastritis (i.e. non-atrophic mucosa) (Fig. 4)

When the overall score for atrophy is 0 in both the

mucosecreting and the oxyntic compartments (meaning that

none of the 5 standard biopsy samples reveals atrophy), the

OLGA stage is obviously 0. The score for inflammatory

lesions is independent of this staging, except in cases judged

indefinite for atrophy, in which case the florid inflammatory

infiltrate may prevent the proper assessment of any loss of

appropriate glands (eventually preventing the Stage assess-

ment). To avoid confounding the issue, all the VAS provided

have been cleansed of any inflammatory component and no

mention is made of any grading of the inflammatory lesions.

The VAS refer to non-atrophic mucosa and are given as a

standard reference to enable comparisons to be drawn withthe pathological VAS.

6.2. Stage I gastritis (Fig. 5)

Stage I gastritis is the lowest atrophic stage. In most

cases (especially in H. pylori-infected patients), atrophic

lesions are only patchy and only found in some of the

biopsy samples available. The atrophy is most frequently

detected in angularis incisura samples. H. pylori status (as

positive or negative) must be explicitly reported as an

essential part of the OLGA format (while a semiquantitative

assessment of H. pylori has little or no clinical impact).

In patients on proton pomp inhibitors [PPI], H. pylori maybe difficult (or even impossible) to identify histologically at

antral or corpus level, in which case coexisting inflammatory

lesions (polymorphs and lymphoid infiltrate) may suggest

the bacteriums presence and a comment on the suspected

bacterial etiology (suspicious forH. pyloriinfection) should

be added (whatever the stage of atrophy recorded ).

Together, Stage 0 and Stage I account for the vast majority

of patients who undergo endoscopy for dyspepsia (with no

alarming symptoms). Neither of these stages have ever been

demonstrably associated with a greater risk of intestinal-type

GC [3]. In cases ofH. pyloriinfection, it is worth considering

treatment to eradicate the bacterium.

6.3. Stage II gastritis (Fig. 6)

This may result from a combination of different (low-level)

atrophy scores, which may concern the mucosecreting and/or

oxyntic mucosa (notably, atrophy is detected in the distal

mucosa biopsy samples in most cases). H. pylori status has

to be reported (see above). From preliminary experience with

OLGA staging, Stage II is frequently found in the low GC

risk epidemiological setting [28]. Notably, Stages 0, I, and II

are those in which duodenal ulcers are more frequent than

gastric ulcers [30].


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Fig. 4. Stage 0 gastritis. All 5 biopsy samples (3 from the mucosecreting compartment and 2 from the oxyntic compartment) consist of normal glands. This

figure shows a normal gastric mucosa in both the antrum and the corpus. Each strip (= 1 biopsy sample) is labeled according to its site of origin (antral/angular= A; corpus = C) and includes 10 glandular units. Any inflammation (lymphocytes, monocytes, plasma cells, granulocytes) is disregarded. The percentages

given on the left refer to the proportion of atrophic glands at single biopsy level (in this VAS, the percentage of atrophy is 0 in all available biopsies). The total

(compartmental) prevalence of atrophy is given on the right, distinguishing between antrum and corpus; the final compartment atrophy score is also shown.

The OLGA staging frame is provided in the bottom right-hand corner, where the OLGA stage is reported (OLGA stage 0). H. pylori-status (as histologically

assessed by special stain) has to be reported.

Fig. 5. Stage I gastritis. Scoring atrophy in each antral/angular biopsy (atrophic glands are identified by a red marker): A1 = 20%; A2 = 20%; A3 = 40%.Assessing atrophy at compartment level (antrum): dividing 80 (= 20 + 20 + 40) by 3 (the number of antral biopsies considered), the final antral atrophy score

(Aas) is 27% (


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Fig. 6. Stage II gastritis. Scoring atrophy in each antral/angular biopsy (atrophic glands are identified by a red marker): A1 = 20%; A2 = 30%; A3 = 70%.

Assessing atrophy at compartment level (antrum): dividing 120 (= 20 + 30 + 70) by 3 (the number of biopsies considered), the final antral atrophy score (Aas)is 40% (>30%


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Fig. 8. Stage III gastritis. Scoring atrophy in each antral/angular biopsy (atrophic glands are always identified by a red marker): A1 = 0%; A2 = 0%; A3 = 40%.

Assessing atrophy at compartment level (antrum): dividing 40 (= 0 + 0 + 40) by 3 (the number of biopsies considered), the final antral atrophy score (Aas) is13% (60%), which means a score of 3.

Combining the atrophy scores for the antrum (Aas = 1) and corpus (Cas = 3) gives us the OLGA stage, as shown in the reference chart (bottom right-hand

corner: OLGA stage III). H. pylori status (as histologically assessed by special stain) has to be reported. In this case, the pattern of atrophic gastritis (corpus

predominant atrophy) should suggest an autoimmune etiology.

Fig. 9. Stage IV gastritis. Scoring atrophy in each antral/angular biopsy (atrophic glands are identified by a red marker): A1 = 70%; A2 = 90%; A3 = 70%.

Assessing atrophy at compartment level (antrum): dividing 230 (= 70 + 90 + 70) by 3 (the number of biopsies considered), the final antral atrophy score (Aas)

is 77% (>60%), which means a score of 3.

Scoring atrophy in each corpus biopsy (atrophic glands are identified by a red marker): C1 = 40%; C2 = 70%.

Assessing atrophy at compartment level (corpus): dividing 110 (= 40 + 70) by 2 (the number of biopsies considered), the final corpus atrophy score (Cas) is

55% (>30%


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Table 3

The histology report: checklist

Section of histology report Recommendations Notes

Biopsy sample identification The biopsy samples should be identified (1,2, 3,

etc., or A, B, C, etc.) as submitted (each vial).

Biopsy location (each vial) should be reported as

submitted (quote the histology request form).

The number of biopsy samples delivered in thesame vial should be reported.

Each biopsy sample should be explicitly associated

with its gastric mucosa subsite (as identified

during endoscopy procedure).

Clinical information The most pertinent clinical information should

be reported (quote exactly from the histology

request form).

When no clinical information is available, this

should be noted (i.e. no clinical information

available).

Histology assessment (description and scoring

of elementary lesions)

Histology assessments should refer to each

available specimen (as previously identified).

The main histology lesions should be scored

according to the current literature (for lymphoid

inflammation and activity, see Gentas visual

analog scales; for atrophy scoring see the present

text). Scoring H. pylori density is irrelevant.

Diagnostic statement This includes OLGA stage and etiological hypothesis (H. pylori, autoimmune, chemical agents or

combinations).

Additional comments If any (the finding of IEN has to be specifically noted and explicitly associated with its gastric

mucosa subsite).

7. How to prepare the histology report

The essential parts of the histology report are summarized

in Table 3.

The material submitted (identified by numbers or letters)

has to be listed according to the gastric sub-site from which

each biopsy sample was obtained. The number of biopsy

samples obtained from each site (and delivered in the same

vial) has to be reported.The available clinical information should be included in

the histology report as provided in the histology request (the

absence of clinical data should be mentioned). The clinical

information mentioned in the histology report should include

the indication for endoscopy, a brief description of endoscopic

lesions (if any), previousH. pylori eradication therapy and/or

other current therapies (NSAID, PPI, etc.).

The assessment/description of the elementary lesions (in

each of the biopsy samples considered) represents the core

element in the histology report. A semiquantitative score

of some of the elementary lesions should be provided, i.e.

(a) lymphoid-monocytic inflammation, (b) polymorphs (i.e.activity), (c) atrophy (distinguished as metaplastic and non-

metaplastic), (d) H. pylori status (positive versus negative).

Other histological lesions (i.e. foveolar hyperplasia, vascular

ectasia) can simply be mentioned. Any advanced precan-

cerous lesions (IEN) have to be reported specifically and

explicitly associated with the biopsy sample(s) where they

were identified.

According to the OLGA staging system, the final assess-

ment should include the stage of gastritis and the etiological

hypothesis, based on the overall gastritis phenotype.

8. Conclusions

Gastritis is assessed by obtaining histological proof of

inflammatory cells within the gastric mucosa. Based on the

definition of atrophy as the loss of appropriate glands, the

recently proposed gastritis staging (OLGA) system may afford

a reliable indication of the cancer risk of individual patients.

Gastritis staging plainly expresses the cancer risk associated

with atrophic gastritis and may help the physician to develop aclinical, serological or endoscopic management plan tailored

to each patients disease.

Conflict of interest

The authors have no conflict of interest to report.

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